Many chronic viral infections in humans and in animal models result in T cell exhaustion. The associated T cell dysfunction has been a major barrier to harnessing the power of T cells during chronic infections. This T cell exhaustion is thought to be driven by high and continuous exposure to viral antigens in the context of immunoregulatory signals from cell surface inhibitory receptors and other regulatory pathways. Understanding the potential for, and mechanisms underlying, reversal of T cell exhaustion is critical information for developing immunotherapies of many human chronic infections as well as cancer. Moreover, any curative interventions for chronic infection will be faced with the question of what type, if any, residual functional immunity will remain. In other words, following cure of chronic infection, does T cell exhaustion reverse? The recent introduction of direct acting antivirals that can dramatically and rapidly lower/eliminate HCV viral replication offers a unique opportunity in humans to investigate whether and how removal of infection allows recovery from T cell exhaustion. Our fundamental hypothesis is that functional "cure" of chronic viral infection will result in reversal of T cell exhaustion that will differ between CD4 and CD8 T cells, will result in population based changes in subsets and/or clonality of exhausted T cell populations and will be impacted by prior IFN-I based treatments. We therefore suggest to address the following specific aims:
Aim 1. To test whether drug-mediated removal of persistent antigen allows recovery from exhaustion and (re)-differentiation into functional effector and memory T cells and whether differences in CD4 versus CD8 T cell exhaustion are associated with different degrees of recovery Aim 2. To test whether functional "cure" of chronic infection leads to population-based selection during "recovery" of exhausted T cells.
Aim 3. To test how the duration of chronic infection and pre-exposure to IFN-a impact recovery of T cells following "cure".

Public Health Relevance

We will test whether and how the T cell response targeting hepatitis C virus can recover after the virus is successfully treated with novel drugs directly inhibiting the virus. This is a unique opportunity to answer a long-standing question relevant for both treatment of chronic infections and cancer in humans: Can existing unsuccessful T cell responses return to a state in which they are more effective in controlling disease?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-LAR-I (J1))
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Massachusetts General Hospital
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